?DESCRIPTION (provided by applicant): Advanced cancer continues to be a major health problem in US and scientific advances suggest that manipulating the immune response may result in effective anti-tumor therapy. This Program is led by an international group of experts in NK cell biology and clinical transplantation. We have studied DNA from thousands of hematopoietic cell transplants facilitated by the National Marrow Donor Program, to correlate donor genetics with transplant outcome using outcome data from the CIBMTR. This is one of the only Program Project Grant focused solely on human NK cell biology and therapy. We have made great progress during the current funding and have made a number of scientific observations that drive the innovation of this revised renewal. We discovered that killer-immunoglobulin receptor (KIR) gene interactions with MHC class I molecules impact clinical outcomes, safely performed the first-in-human testing of IL-15 and IL-15/IL-15R?-Fc superagonist complexes, developed strategies to make NK cells specific for target antigens and discovered unique properties of CMV-induced adaptive NK cell in humans with memory like properties and altered function. Transplant donors and cancer patients can be defined by NK cell receptor genes of the KIR A or B haplotype. During the current period of support we found that unrelated donors with favorable KIR genes confer significant relapse-free survival benefit to transplanted AML patients containing at least copy of HLA-C1. Project 1 (Peter Parham) will focus on the functions of KIR B haplotype genes using novel functional assays to precisely interrogate interaction with MHC using mass cytometry. He will expand KIR analyses by high resolution sequenced typing in AML cohorts. This will yield an unprecedented high resolution of immune reconstitution after transplant. In Project 2, Jeffrey Miller discovered that NKG2C+ NK cells expand in vivo with CMV reactivation resulting in NK cells with specialized function through CD16 with enhanced cytokine responsiveness. He will test whether CMV-induced adaptive NK cells are better equipped to treat cancer compared to conventional NK cells. In Project 3, the clinical outlet of this Program, Daniel Weisdorf will 1) Use KIR typing for choosing favorable unrelated transplant donors, 2) Test NK cells in a randomized trial, and 3) Target NK cells specifically to AML and MDS by the use of bi-specific killer engagers (BiKEs). The research in the Projects will be supported by the Administration and Clinical Research Support (Core A), Biostatistics (Core B), our unique Bioinformatis and Data Management teams (Core C) and our Immune Moitoring and BiKE Production (Core D) resources. This Program will establish definitive roles for NK cells and their receptors in allogeneic transplantation with broader impact to all cancer therapy.